In recent experiments, combination DNA priming/protein boost vaccination regimens have elicited protection against challenge with chimeric SHIV in juvenile and neonatal vaccine recipient macaques. The experiments propose din Project 3 will test whether protection against a SHIV construct encoding a clade C env gene (SHIVenvC) can be achieved in both juvenile and neonatal macaques using a DNA prime/protein boost schedule of vaccination. The main points of Specific Aims of Project 3 are: 1. To test the immunogenicity of codon-optimized HIV-I clade C env- and SIV gag-pol-expressing plasmids in mice (Specific Aim 1a). Nest, we will test the safety and immuno genicity of the most immunogenic DNA plasmids in juvenile (Specific Aim 1b) and neonatal macaques (Specific Aim 1c) using a DNA prime/protein boost strategy. We will vaccination against both HIV-I clade C env gp160 and SIV Gag-Pol. 2. To test whether DNA prime/protein boost can induce protective immunity in juvenile macaques against i.v. challenge with homologous SHIVenvC1. Immunized juveniles from Specific Aim 1b will be challenged i.v. with SHIVenvC1. Viral load will be assessed by co- cultivation of PBMC and by RT-PCR of plasma. Pathogenicity will also be assessed. 3. To test whether DNA prime/protein boost can induced protective immunity in macaque infants vaccinated as newborns against oral challenge with SHIVenvC1. As a model for postnatal mil borne virus transmission immunized animals from Specific Aim 1c will be challenged at one year of age by oral inoculation with SHIVenvC1. 4. To test if protected animals in Specific Aims 2b and 3b have developed broad, protective immunity against divergent SHIV isolates expressing heterologous Env glycoproteins. 5. To test whether active + passive immunization can induce protection against systemic infection for infant rhesus macaques challenged orally at birth with SHIVenvCV1. The experimental results of Project 3 are integral to the overall goal of the Program Project to develop passive + active immunization to prevent virus transmission at birth and through breast feeding. The findings of this Project will have clinical relevance for HIV clade C endemic areas of sub- Saharan Africa.